1,1′-Spirobiindane-6,6′-diol derivatives of Structure I:
have recently found substantial utility as, among other things, precursors for chiral polymers as disclosed in U.S. Pat. Nos. 5,856,422A and 6,288,206B1, precursors for macrocyclic compounds as disclosed in B. Kohler, et al., Chemistry—A European Journal, 7(14), 3000 (2001), precursors for chiral cyclophanes as disclosed in G. A. Consiglio, et al., Journal of Supramolecular Chemistry, 2(1–3), 293 (2003), and, more recently, precursors for the preparation of novel chiral dopants for nematic liquid crystal formulations as disclosed in U.S. patent application Ser. No. 10/737,457. Many of these applications require the use of enantiomerically enriched 1,1′-spirobiindane-6,6′-diol derivatives.
Methods for the efficient, environmentally responsible, large-scale preparation of these nonracemic derivatives are limited. Many syntheses of racemic 1,1′-spirobiindane-6,6′-diol derivatives have been disclosed, for example, in U.S. Pat. Nos. 4,701,566, 4,701,567, 4,791,234A, 6,132,641A, DE2645020, DE4027385, J. Chem. Soc., 1962, Revista Chimie, 34, 1069 (1983).418. J. Org. Chem., 55, 4966(1990), J. Med. Chem., 43, 2031(2000), and J. Amer. Chem. Soc., 122, 2055(2000). These methods necessarily provide a 1:1 enantiomeric mixture of the derived 1,1′-spirobiindane-6,6′-diols. While methods for separating these mixtures do exist, they have proved wanting (vide infra).
Four general methods for the isolation of nonracemic compounds are known to those skilled in the art of organic chemistry: 1) chiral synthesis of individual enantiomers, 2) chiral chromatographic separation of racemates, 3) enzymatic resolutions of racemates, and 4) use of chiral auxiliaries for diastereomeric formation eventually leading to enantiomer separation. No methods for the direct synthesis of individual 1,1′-spirobiindane-6,6′-diol enantiomers are known. Further, the separation of racemic mixtures into their constituent enantiomers via chiral chromatography is primarily an analytical technique. While such technology for the “preparative” separation of racemic mixtures does exist, it is generally limited to a maximum of several grams of material, less than needed for many commercial applications. Further, the technology for these preparative separations is limited in structural scope, not readily allowing separation of the desired 1,1′-spirobiindane-6,6′-diol derivatives.
A method for the enzymatic separation of the enantiomers of a 1,1′-spirobiindane-6,6′-diol derivatives has been reported by R. J. Kazlauskas U.S. Pat. No. 4,879,421 and Journal of the American Chemical Society, 111(13), 4953–9(1989). This methodology employs (1) the preparation of achiral esters of the racemic 1,1′-spirobiindane-6,6′-diol derivatives, (2) the enantio-selective enzymatic hydrolysis of these racemic mixtures and (3) the eventual isolation of substantially enantiomerically enriched samples of the requisite 1,1′-spirobiindane-6,6′-diol derivatives after achiral chromatographic purification. While this technology has been demonstrated to be useful in the preparation of hundreds of grams of nonracemic 1,1′-spirobiindane-6,6′-diol derivatives, it suffers from substantial drawbacks. The initial step of Kazlauskas resolution requires the synthetic preparation of ester derivatives of the racemic 1,1′-spirobiindane-6,6′-diol. This material is then exposed to an appropriate enzyme formulation in aqueous media for several days. During this reaction phase, care must be taken to control reaction temperature and solution alkalinity. Careful analysis of reaction composition is also needed to alter reaction conditions, thus ensuring optimal conversion to nonracemic product. With the completion of the enzymatic reaction, multiple solvent extractions provide a nonracemic residue that must be further purified. Achiral silica gel chromatography, employing the environmentally suspect methylene chloride as an eluant, then provides the nonracemic products. Finally, saponification of residual ester groups provides the desired 1,1′-spirobiindane-6,6′-diol in good overall yield and high racemic purity. Application of this protocol to multi-kilogram production is limited, among other factors, by extended reaction times, multiple extractions leading to excessive solvent waste, large scale chromatographies, and the use of environmentally unacceptable chlorinated solvents.
Japanese chemists previously described the separation of a 1,1′-spirobiindane-6,6′-diol derivative using diastereomer formation, Bull. Soc. Chem. Japan, 44, 496 (1971). In that case, the requisite racemic spirobiindandiol substrate was reacted with a nonracemic chiral isocyanate to yield a mixture of diastereomeric mixture of urethane products. The mixture was then purified by repeated recrystallizations from benzene, a solvent designated a cancer suspect agent by the EPA. Finally, the desired spirobiindane was secured by chemical degradation of the chiral urethane groups.
Esters of phenols in general are very commonly encountered organic compounds. Within this context, they are meant to include structurally those derived from a 1,1′-spirobiindane-6,6′-diol and a carboxylic acid component. The acid component can be alkyl, cycloalkyl, aryl, alkyloxy (alkylcarbonic acid), cycloalkyl (cycloalkylcarbonic acid), or aryloxy (arylcarbonic acid). General methods for the preparation of phenyl esters are apparent to those skilled in the art. These method include: (1) reaction of the phenol with an acid chloride under basic conditions; (2) reaction of a phenol with a carboxylic acid under acidic conditions; (3) reaction of the phenol with a chloroformate; (4) reaction of a phenol and a carboxylic acid using a condensing agent; (5) reaction of the phenol with phosgene to prepare an intermediary phenyl chloroformate, that then can be condensed with a second phenol or alcohol, and similar transformations.
A variety of nonracemic chiral carboxylic acids, acid chlorides, chloroformates, and alcohols are available for the preparation of esters of potential use in separating 1,1′-spirobiindane-6,6′-diol enantiomers. These substrates may in turn be derived from natural sources, isolated chromatographically, prepared via enantio-selective methods, or otherwise purified. Most commonly, natural product derivatives are employed as chiral auxiliary agents.